Ras-GRF1 is a
guanine nucleotide exchange factor
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...
. Its function is to release
guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine.
GDP is the pr ...
, GDP, from the signaling protein
RAS, thus increasing the activity of RAS by allowing it to bind to
guanosine triphosphate
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only di ...
, GTP, returning it to its active state. In this way, Ras-GRF1 has a key role in regulating the
RAS signaling pathway. Ras-GRF1 mediates the activation of RAS via
Ca2+ bound
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
protein.
Function
Activation of Ras proteins occur through the phosphorylation of tyrosine receptors. This recruits adapter protein GRB2 which binds to SOS exchange factors, that bind and activate Ras. Ras/MAPK pathways is activated by the intracellular calcium that binds to the ilimaquinone domain (IQ) on Ras-GRF1. Activated Ras can go on to activate Raf/Mek/Erk kinases which can mediate the activation of CREB transcription factors. This can affect gene expression and cell proliferation.
Ras-GRF1 knockout mice have been shown to have learning and memory deficits associated with dysregulation of this pathway. Ras-GRF1 has also been shown to be upstream from
IGF1, allowing it to control growth in mice. Although it is sometimes known as CDC25, it should not be confused with
Cdc25
Cdc25 is a dual-specificity phosphatase first isolated from the yeast ''Schizosaccharomyces pombe'' as a cell cycle defective mutant. As with other cell cycle proteins or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell divis ...
. Ras-GRF1 is a paternally expressed
imprinted gene
Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the female or male parent. Genes can also be partially imprinted. Partial imprinting occurs when alleles from b ...
, meaning that only the paternal
allele
An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule.
Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
of the gene is translated into protein. Disruption of this epigenetic imprinting also produces learning and memory deficits in neonatal mice.
Ras-GRF1 has been shown to mediate
long term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...
(LTP), affecting memory and learning. A signaling pathway involving Ras-GRF1/
p38 MAP/
CP -AMPAR has been shown to affect LTP. Ras-GRF1 knockout mice, induced with high frequency stimulation to induce LTP (HFS-LTP), displayed the inability to retain memory and distinguish similar concepts.
A Ras-GRF1/
ERK pathway has also been found to affect the activity of LTP in
medium spiny neuron
Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of inhibitory GABAergic neuron representing approximately 90% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons h ...
(MSN) pathways. Ras-GRF1 knockout mice treated with HFS-LTP have exhibited the inability to induce LTP in direct MSN pathways. Ras-GRF1 signaling has been thought to be involved with
L-DOPA-induced dyskinesia, a condition in which LTP and MSN homeostasis are disrupted.
Alongside its regulation of learning and memory, Ras-GRF1 has exhibited the ability to impact pancreatic
β-cell proliferation. Ras-GRF1 knockout mice have expressed decreased pancreatic β-cell concentration and activity. Reduction of β-cell mass and area has correlated to a decrease in circulating
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
levels, exposing a Ras-GRF1 signaling pathway that regulates
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
metabolism.
References
External links
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{{GTP-binding protein regulators